The treatment of most central nervous system (“CNS”) diseases faces two issues: (1) developing therapeutics that treat the actual cause of the disease and (2) getting therapeutic agents to the CNS across the blood brain barrier (“BBB”). Regarding the first issue, most agents seek to ameliorate the effects of the particular disease rather than treat the actual cause of the condition, which may be the loss or abnormal activity of particular neurons necessary for normal brain function. For instance, the available drugs on the market for Parkinson's Disease mimic or replace the lost dopamine, but do not get to the heart of the problem, which is the progressive loss of the dopamine neurons (see, e.g., LeWitt and Taylor, (2008) Neurotherapeutics. 5:210-225). As such, therapies that protect against loss of neuronal populations would be an advance over present therapies that are available for many diseases.
One potential therapy is gene therapy. Gene therapy has been shown to be effective to treat certain diseases by allowing abnormal cells to function normally. Such therapy can be gene replacement, wherein a normal copy of the disease-causing gene is introduced into affected cells. Such disease-causing genes are typically aberrant due to gene mutation, but levels of gene expression due to mutations in gene expression control regions, or in transcription factors, may result in the pathogenesis of disease. Alternatively, gene therapy can introduce a nucleic acid that expresses a therapeutic protein which improves the survival or function of cells that are vulnerable to a disease process without correcting the underlying cause of the disease. Such disease-modifying nucleic acids are not gene replacement. And gene therapy also can introduce or express an anti-sense moiety, thereby reducing levels of disease-inducing RNAs and proteins. An example of gene replacement therapy is the treatment of cystic fibrosis by providing the cystic fibrosis transmembrane conductance regulator (CFTR) gene to lung cells that do not have a normal copy of this gene (see Griesenbach et al. (2004) Gene Therapy 11: S43-S50; Konstan M W, Davis P B, Wagener J S, Hilliard K A, Stern R C, Milgram L J H, Kowalczyk T H, Hyatt S L, Fink T L, Gedeon C R, Oette S M, Payne J M, Muhammad O, Ziady A G, Moen R C, and Cooper M J. (2004) Human Gene Ther, 15:1255-1269.). An example of gene therapy to improve survival of vulnerable or damaged cells is the treatment of Parkinson's disease with a gene for a neurotrophic factor (see Bjorklund et al., (2000) Brain Res. 886: 82-98; Hurelbrink and Barker, (2004) Exp. Neurol. 185: 1-6.). Nevertheless, these therapies have faced the hurdle to get the gene therapy to the proper cells, and to get the cells to produce the therapeutic protein at appropriate levels, even without the BBB acting as a barrier to getting therapeutics to the proper cells (id.).
Regarding the issue of the BBB, one technique employed in the prior art has been intracranial injection of therapeutics into the brain. For example, glial cell line-derived neurotrophic factor (“GDNF”) protein has been injected into the brains of Parkinson's disease patients (see, e.g., Gill et al. (2003) Nature Med. 9: 589-595; Lang, et al. (2006) Ann. Neurol. 59: 459-466.). Similarly, the gene for neurturin, a GDNF analog, has also been injected into the brains of Parkinson's patients (see, e.g. Marks Jr et al. (2010) Lancet Neurology 9: 1164-1172). As for most gene therapies, the neuturin gene was inserted into a viral vector that helps get it into cells. The technique of intracerebral injection and the use of viral vectors pose safety risks such as potential damage to brain tissue, hemorrhage, immunogenic reactions to the viral vector, and issues relating to infection and the inherent trauma associated with brain surgery. Furthermore, such injections often treat only the cells within a few millimeters of the injection track. To treat a wider area requires multiple injection tracks which increase the likelihood of certain safety risks such as hemorrhage and potential damage to brain tissue. If the disease requires treatment of a large segment of the CNS, the risks of numerous injections are of concern; especially if one or more large areas involving multiple structures such as cerebellum, brainstem and cerebrum need to receive treatment.
Accordingly, there remains a need for methods and formulations that allow for the treatment of the causes of neurodegenerative diseases without necessitating direct injection (often multiple injection tracks are needed for even a small defined area of treatment) into the brain or the need for viral vectors. In addition, there remains a need for methods and formulations that allow for therapeutics to circumvent the BBB to safely and effectively get therapeutics to the CNS.